MPNforum Magazine

Introduction:

The MPN patient’s choice between stem cell transplant and a clinical trial isn’t often made in time of crisis.  Usually, we have months or even years to consider stem cell transplant or clinical trial. I’ve been doing it for five years…and still haven’t decided.

Over time, I’ve assembled some facts, exhibits, notes, observations and prejudices along the way.   Sharing this collection might help other patients sort out their choices and clarify the nature of these two (usually) end-stage treatment options.  I have seen friends choose a long clinical trial and advance to blast stage myelofibrosis. Many friends have come out the other end of stem cell transplant, whole, cured of MF and free of infection and Graft Versus Host Disease (GVHD). Some did not.

No one, however, has come out of any MPN clinical trial cured.  Some have experienced symptomatic relief, a few have been injured or died in the course of the clinical trial. (See Sanofi, Imetelstat below.)  But the choice is far from a draw.  Stem cell transplant may be risky but it’s essentially a medical procedure.  Clinical trial is much safer but always an experiment, a trial of drugs of unknown efficacy placed in human systems of incompletely understood genetics and biochemistry..

What follows is a personal view of the current  state of MPN clinical trial and some current SCT perspectives.  The choice of one or the other, made with the counsel of a competent, caring hematologist, may lead to many years of high quality, active life. The choice is deeply personal and dependent on factors unique to each of us.

Stem cell transplant vs. Clinical trial – an exploration of sorts

“I’m pretty healthy, relatively young. I have some options. What’s best, stem cell transplant (SCT) or clinical trial?” Head for the Facebook MPN pages and you’ll find some version of that post.

Recruitment for several new clinical trials and publication of an encyclopedic summary of SCT experience is an opportunity for us to step back and consider our real treatment options when faced with a definitive choice.  It’s also a chance to explode some myths that have been floated to obscure the realities of those treatments.

Soon, we will have immunotherapy and gene editing options. For now, once drugs have failed,  patients with high risk myelofibrosis  and acute myeloid leukemia often face a stark choice:  Clinical trial,  Stem cell transplant (SCT) or simply wrap up affairs and prepare to die as well as possible.

Why it’s so hard to choose

It is an agonizing decision, a decision that holds one’s life in the balance. Rarely do we or our doctors have the full information necessary to make a rational decision.  We are forced to rely on professional advice,  our bias, our gut feeling.  Even improved medical diagnostics cannot remove all uncertainty. Despite published  survival rates, prognostic  scoring systems, charts and graphs and symptom evaluation forms, there is still our singularity.

We respond differently to drugs. Our genetics are individual, our immune responses singular. And medical tests and interpretations of results far from consistent.

We can reduce our uncertainty by factoring in some broad measurements:  age, clinical condition, availability of a likely trial drug or a perfectly matched donor, and affordability.  Often any of those factors may disqualify us for clinical trial or stem cell transplant.

For death, we are all finally qualified To choose to die instead of submitting to treatment can be a rational decision to accept the inevitable or simply forego pain, discomfort, expense and disability to briefly extend a life of poor quality .

Beyond the rational, our biases are strong.

We are influenced by the evidence right before our eyes, friends who have survived SCT and are thriving, or have suffered GVHD or died; friends injured in clinical trials, booted off or doing well on a trial drug . Generally,  patients believe a clinical trial is a much safer, more reasonable option than a risky stem cell transplant. While there are no cures coming out of the countless MPN clinical trials, there are also few drug-related deaths or long-term debilities.   Part of the price we pay in clinical trial is stressing our immune system, risking serious side effects and losing valuable time — time during which myelofibrosis or AML progresses, blast levels increase,health deteriorates and odds of a successful stem cell transplant fall..

Fundamentally, stem cell transplant is a medical procedure that may include some experimental activities or medications while clinical trial is an experiment that incorporates several medical procedures.

In SCT, given  known parameters – patient age and condition, donor source, donor match, experience of transplant team – a reasonable estimate of success is possible. The stages are clearly understood — induction, consolidation, transplantation and  maintenance — based on the experience of more than one million transplants.  The risk/benefit proposition is simple: You risk injury and lifelong GVHD for the possibility of a full, complete cure.  Between those two poles there are shades of gray.

On the other hand,  every phase of every clinical trial is an experiment on human subjects, the testing of a hypothesis previously demonstrated in test tubes, mice and perhaps other humans: dosage, response, efficacy, toxicity…all unknown until the Phase 3 double blind comparative studies…and sometimes even then.

(Famously, in 2013 the Sanofi large scale trial of fedratinib blew up on the eve of its application for FDA approval, at the end of Phase 3. And more than 6% of FDA approved drugs are later recalled for safety issues.)

 The risk/benefit proposition in clinical trial is the chance to get an effective drug and high level medical care free for life with minimal risk of injury since the trial is overseen by regulators, doctors, an institutional review board and a data monitoring committee.

The Leukemia and Lymphoma Society publishes an advisory that represents the ideal:

Patients in clinical trials are watched closely by their doctor, as well as by other members of their medical team, to ensure their safety. Every trial has a precise treatment plan called a “protocol,” which must be followed. Patients get a lot of attention and receive excellent cancer care. The trial can be changed or stopped if there is a problem. Patients who take part in a clinical trial also have the option to leave the trial at any time.

The reality behind the clinical trial game is less straight forward, more like a glitzy casino on the Vegas Strip with bright lights and a bank of busy slot machines.  The process is long, highly publicized and expensive,  often costing several hundred millions of dollars for a full blown trial.   Money, influence. competition, and small chance of success characterize and influence the great majority of clinical trials in which fewer than 8% make it through to FDA approval at the end.  To patients and their families, clinical trial may appear  in white lab coat in a hospital setting  but it’s a very high stakes money game in which human subjects are needed to explore the healing properties of a hopefully marketable molecule. Add to all that the interested subjectivity of those preparing trial reports.

In early phase clinical trials, patients are dosed and measured, probed and recorded after receiving escalating or varying doses of a substance whose precise mechanism of action is rarely, if ever, known.  In later stage double blind clinical trials there’s no guarantee that for all the patient’s pain, risk, inconvenience and expense the experimental drug, and not a placebo, will even be administered.

For patients the appeal is obvious  as is the danger.

The appeal to patients is the appearance of high level, free medical care at a highly respected medical facility and a free miracle drug for life (if it works). Patients, often with few treatment options have little choice…and basically no rights. It would be nearly impossible for them or their survivors to sue in cases of severe negligence, failure to report signals of toxicity, etc. Meantime,  during the course of the trial,  myelofibrosis continues to progress, blast cells multiply, organs swell and the human immune system is stressed.

Six men hospitalized, three with irreversible brain damage and one declared brain dead, after drug trial in France.   New York Times 

The clinical trial medical mask has slipped considerably as a result of the Sanofi trial of fedratinib (SAR302503). In this Sanofi trial of a likely good JAK inhibitor acquired from TargeGen,  patients died, were irreversibly injured and principal investigators kept in the dark.

Clinical trial — human medical experiments on trial.

The rigid laws regulating privacy and trade secrets in the clinical trial human experiments, enforced by the FDA, secure drug manufacturers, research organizations and investigating institutions against discovery proceedings.  It took two MPNforum rejected Freedom of Information Act requests plus one rejected FOIA appeal to understand how impenetrable the iron curtain of secrecy surrounding these medical experiments is. In some cases even the clinical trial’s supervising boards and principal investigators are not aware of the adverse events taking place in this human experiment.

Still…what are our odds in considering SCT vs. clinical trial?

For all its warts and wobbles, clinical trial may not offer as great a hope of success as SCT but certainly involves much lower risk, both short and long-term.

“Until November 2011, there were no FDA-approved drug therapies for MF, and most patients received ‘conventional’ treatment when they were substantially symptomatic, in particular as a consequence of worsening cytopenias and splenomegaly. Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only treatment approach which can offer a possible cure, but it is associated with not insignificant risk of morbidity and mortality. Thus, the risk of allo-HCT in low- or intermediate-risk patients and older patients who typically suffer from multiple comorbidities may not be justified. Indeed, the 1-year treatment-related mortality and overall survival (OS) associated with conventional-intensity conditioning allo-HCT are estimated at 30% and 50%, respectively. In addition, 3-year disease-free survival, OS, and treatment-related mortality have not been shown to be favorably affected by reduced-intensity conditioning (RIC)…  This study suggests that allo-HCT with RIC and an HLA-matched related donor remains a reasonable therapeutic approach in select MF patients with advanced disease and anticipated significantly abbreviated survival. Studies such as these indicate the need for a risk-benefit assessment of the use of allo-HCT versus ‘conventional’ or investigational pharmacotherapy”

Biology and Clinical Management of Myeloproliferative Neoplasms and Development of the JAK Inhibitor RuxolitinibJ Mascarenhas,¹ TI Mughal,² and S Verstovsek^{* ,}

 Pasquini MC, Wang Z. Current use and outcome of hematopoietic stem cell transplantation: CIBMTR Summary Slides, 2013.  This is a Powerpoint slide presentation, graphics.

Toxic Effects

A drug-related death in the imetelstat trial

“At the data-cutoff date of December 5, 2014, treatment had been discontinued in 25 patients (76%); the median duration of treatment for all study patients was 8.6 months (range, 1.4 to 21.7). Causes of treatment discontinuation included insufficient response (16 patients); disease progression or relapse after an initial response (3 patients); death during the treatment period (2 patients), including 1 death due to intracranial hemorrhage that was attributed by the treating physician to drug-induced grade 4 thrombocytopenia after weekly dosing (boldface added) and 1 due to an upper gastrointestinal hemorrhage that was not considered to be drug-related; adverse events (2 patients) in the form of persistent thrombocytopenia; and other reasons (2 patients), including financial constraints in 1 patient and a preexisting condition (atrial fibrillation) in 1 patient.”  Tefferi, et al., NEJM, Sept., 2015

Despite a formidable record of failure, clinical trials of MPN drugs and combinations of drugs enjoy enormous support among health providers and MPN support organizations. Try a Google search on “MPN clinical trial outcomes” and see page after of websites advertising available clinical trials. Listings by the institutions running trials and patient advocacy groups supported by drug companies creates a Craig’s List of offerings that don’t tempt patients. Many believe clinical trial is our only path to a cure. It is a path littered with pain and failure, necessary perhaps in the absence of fuller genomic and biochemical knowledge, but clearly a placeholder until trials can be executed in the body of computers.

Despite the drumbeat of support for clinical trials, the rate of  patient participation – enrollment – has fallen as patients recoil at the risk associated with the trial and fear of entering a trial only to be treated on the placebo arm..

The New York Times published  “Do clinical trials work,” in 2013 written by Clifton Leaf, executive editor of Fortune and award-winning medical/science writer.  In writing of the popular drug Avastin Leaf writes: “

“Indeed, even after some 400 completed clinical trials in various cancers, it’s not clear why Avastin works (or doesn’t work) in any single patient. “Despite looking at hundreds of potential predictive biomarkers, we do not currently have a way to predict who is most likely to respond to Avastin and who is not,” says a spokesperson for Genentech, a division of the Swiss pharmaceutical giant Roche, which makes the drug.

“That we could be this uncertain about any medicine with $6 billion in annual global sales — and after 16 years of human trials involving tens of thousands of patients — is remarkable in itself. And yet this is the norm, not the exception. We are just as confused about a host of other long-tested therapies…Which brings us to perhaps a more fundamental question, one that few people really want to ask: do clinical trials even work? Or are the diseases of individuals so particular that testing experimental medicines in broad groups is doomed to create more frustration than knowledge? Researchers are coming to understand just how individualized human physiology and human pathology really are.”

Still the recruitment of patients continues to soar. It is the engine that drives the multi-trillion dollar drug industry.

 

Stem Cell Transplant at a glance

The popularity of stem cell transplant in all applications is increasing as outcomes have significantly improved.

In December 2012, the one-millionth blood stem cell transplant worldwide was performed. (Hematopoietic Stem Cell Transplantation—50 Years of Evolution and Future Perspectives.)

Outcomes—Reducing Transplant-Related Morbidity and Mortality

Hematopoietic stem cell transplantation-50 years of evolution and future perspectives. – PubMed – NCBI/

A set of slides on mortality statistics, demographics and long-term survival of SCT, produced by the Center for Bone Marrow Transplant research is available here.http://www.cibmtr.org/ReferenceCenter/SlidesReports/SummarySlides/Documents/2013%20Summary%  (MPNs are not listed although AML and ‘Other leukemias” are charted.)

Exploration/Discussion

By calling them Clinical Trials an air of sobriety, judgment, and hard evidence surrounds what are essentially experiments on human subjects.

Patients participating in these experiments are generally under the delusion that these exercises in testing alternatives are performed for their benefit.  In fact, they are almost always corporate sponsored events, often costing many millions of shareholder dollars, staged in hope of enormous profit. That nearly all fail is not surprising since the hypotheses on which they’re founded require a knowledge base that just doesn’t exist,.They are testing their best guesses on human beings.

And if we find ourselves numbered among the patients enrolled in the experiment, it is simply because other guesses at treatment alternatives failed to stop our disease from progressing.

The terrible success rate of these experiments would improve, of course, if Sponsors were held responsible for the outcomes of these human experiments.  If a patient is severely injured or dies as a result of the molecule being tested, then the Sponsor would be liable for damages or, in case of negligence, criminal prosecution. In fact, however, it’s all a zero risk game for drug companies. If a drug is moderately successful  – or can be made to look like it has some worthwhile activity —  it is approved, put on the market and profits are reaped by the Sponsor.  If the drug utterly fails, patients are injured or die, the experiment is aborted, the records are sealed under Federal privacy regulations, and it’s on to the next rodeo.

Medical decision making – To treat or not to treat

After diagnosis, our first decision is whether to treat aggressively or monitor conservatively..Against the arguments for Watch & Wait, for holding off treatment until the characteristics of our MPN become established  are strong arguments to treat early, when the disease is more responsive to drugs.

The problem with that argument is starkly clear: The third leading cause of death in the United States are mistakes made in medical treatment.

Imprecise medicine

Additionally, without taking into account our unique genetic profile – and perhaps even then — we just cannot know with any certainty the effect of any drug. All reports without exception indicate we have uneven rates of response to drugs, the basis for Precision Medicine.As things stand, we simply don’t have the data to predict how we would react to a drug.

After drugs fail

Nowhere is medical decision making more urgent and have more bearing on our longevity and perhaps survival than at advanced disease stages, after meds fail and disease progresses. When the pain and discomfort start.

Stem cell transplant or clinical trial

For many of us the decision resolves to a simple choice: stem cell transplant or clinical trial.

The factors in making this decision are well known. If we qualify for SCT by virtue of age and clinical condition then the most essential elements are state of health, the availability of a closely matched donor and the availability of an experienced, successful transplant team.  That last is also a function of distance, economics, insurance, family support and other non-medical factors. (Medicare’s approval of national coverage of MF SCT last month (See TSR, this issue) has eased concern over one of those issues.)   Each factor has to be considered in assessing risk versus potential benefit…and the likely odds of success. In its favor, the stem cell transplant for blood disease has rapidly increased its success rates lowering risk by use of novel agents in induction therapy, improved supportive care to prevent severe infections and the use of reduced-intensity conditioning protocols allowing for transplantation in older patients.

Clinical trial without blinders

Clinical trial provides a different decision set.   We are attracted to clinical trial through the miracle cure/silver bullet appeal, a promise of free drugs, and high level supervised care.  Beyond inconvenience and expense of travel, long clinic waits, and other administrative chores, this is almost never the actual outcome.

While the so-called gold standard double blind phase 3 multiple site trials might be an option, any Phase 1 trial, in which progressive doses of a drug are administered until signs of toxicity emerge should probably be ruled out in all but the most desperate cases. These are the first human experiments after animal trials. Phase 2 trials, where the drug is tested on a larger cohort of humans for safety and efficacy is where most new drugs fail. Whether for lack of therapeutic effect or unanticipated toxicities, there’s usually no reason for us to volunteer to find out.

If we decided to enter one of the gold standard clinical trials of new drugs in the past couple of years,we would have lost our bet and lost time while running the risk of injury or death. .From a purely observational perspective, clinical trial has many negatives to factor into the decision process. The sad truth is clinical trials will almost always fail and we will hardly ever get a full report of the results as required by law.

Along with its abysmal record of success in producing effective drugs, the clinical trial option is also clouded by misrepresentation, secrecy, manipulation, and statistically inevitable false positive effects. And while the high failure rate is problematical for drug companies, it is deadly for MPN patients who lose time and health resources while incurring new possible sources of inflammation and physiological insult due to trial drugs.

Improving our odds

Finally, we can tilt the odds in our favor by partnering with a compassionate, skilled, MPN specialist. If we’re lucky. One downside of a rare disease is specialists in that disease are even rarer.  Developing our own deep knowledge of our disease – at the very least its signs, symptoms and treatment options – and actively participating in our care is essential to ease the burden on a harried, overbooked physician and assure all our known options are being factored into our medical decision matrix.

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